Use of adamantane amines or structurally similar compounds for combating borna disease virus and for the prevention and treatment of affective diseases and other disorders associated with bdv infections in humans and animals

ABSTRACT

The invention concerns the use of 1-adamantane amines (amantadines) or structurally similar compounds for combating borna disease virus infections and for treating affective diseases and disorders associated with borna disease virus infections in humans and animals. The use of these substrates results in rapid and lasting elimination of the symptoms and signs and in the suppression of the virus activity.

This application is a 571 of PCT/DE97/92455, filed Oct. 23, 1997, whichclaim the priority of German application 1964498.7, filed Oct. 30, 1996.

BACKGROUND OF THE INVENTION

The invention relates to adamantane amines or structurally similarcompounds for combating the Borna disease virus and for the preventionand treatment of emotional diseases and other disorders associated withBDV infections in humans and animals.

Emotional diseases, in general, and depressions of different severities,in particular, are among the most widespread syndromes at the presenttime, at least in industrialized countries. It is estimated that, forexample in Germany, approximately 5% up to possible 10% of thepopulation suffer at least occasionally from depressive diseaseconditions. These conditions are not merely mild emotional upsets; theyare diseases, which severely affect the afflicted and can make themunable to work and this, not only if the condition exists for a longertime. The suicide rate for endogenous, depressive patients at thepresent time is of the order of 20%, if medical help is not sought.Frequently therefore, prolonged in-patient treatments are unavoidablewhich, in turn, is a problem for the patient as well as for the generalpublic.

In the case of a longer in-patient treatment, the danger ofhospitalization exists for the patient. Moreover, society must makesufficient therapy places available, including suitable clinics andspecially trained personnel. All this is also associated with high costsfor the general public.

It is now known that not only man, but also animals can suffer fromemotional disorders in a similar manner. Such disorders are known, forexample, for horses, in which the syndrome expresses itself as alistless phase, which is associated with drowsiness, loss of energy andfrequently with disorders of muscular coordination. This horse diseaseis associated with an activated Borna disease virus infection. In theextreme case, the diseased animal must be put to sleep in order to bringan end to its suffering.

Depressions are also treated with drugs. On the basis of differenttheories, an attempt is made to influence the nervous system and toimprove the depressive symptoms. Various anti-depressive drugs can havea mood-elevating, psychomotor-activating, calming or anxiety reducing,etc. effect to different degrees. The mode of action of most of thedrugs has been clarified only inadequately.

For example, tricyclic and tetracyclic drugs are in use. According toother therapeutic attempts, selective seratonin reuptake inhibitors(SSRI), monoamino oxidase inhibitors or noradrenalin reuptake inhibitorsare administered therapeutically. Many drugs have relatively severe sideeffects, such as the danger of convulsions, tremors, nausea andvomiting, headaches, anxiety states, severe liver and kidney disorders,anemia, etc. Moreover, the anti-depressive effect is limited orsubjectively not present in a number of patients.

There is therefore a great need for a more effective medicinaltreatment, and moreover for one with fewer side effects, for thetreatment of emotional disorders of different origin.

Recently, the Applicants were able to find virus proteins and geneticmaterial of the Borna disease virus (BDV) in the blood samples ofemotionally sick patients during an acute depressive phase. This geneticmaterial comprised sheathed, non-segmented, single-strand RNA virus ofnegative polarity, which is known to initiate emotional and, in somecases, depression-like symptoms in animals. It was possible to isolatethe infectious human BDV from the blood of patients with differentintensities of emotional diseases (L. Bode in Curr. Topics Microbiol.Immun. 1995, 190, 103-130; L. Bode, W. Zimmermann, R. Ferszt, F.Steinbach, H. Ludwig, Nature Med. 1995, 1, 232-236; L. Bode, R.Dürrwald, F. A. Rantam, R. Ferszt, H. Ludwig, Mol. Psychiatry 1996, 1(3): 200-212).

It may be assumed that a BDV infection, aside from other factors, suchas possibly a genetic predisposition, could represent a factor in theinitiation of emotional diseases, which are characterized, for example,by changes in the messenger material area of the limbic system and couldrepresent other, especially cerebral, disorders.

The problem, on which the invention is based, consists therein thatdepressions in man and animals are to be treated medicinally, aseffectively as possible, without significant compromising side effects.At the same time, any BDV infection present should, if possible, besuppressed effectively or eliminated. Moreover, BDV infections in manand animal in general are to be controlled.

SUMMARY OF THE INVENTION

In order to solve this problem, the invention provides for the use ofadamantane amines or compounds of a similar structure.

The inventive use is indicated for the prevention and control of virusesof the Bornaviridiae family, especially Borna disease virus (BDV)infections and for the treatment of emotional disorders and otherdisorders associated with Borna disease virus infections in humans andanimals.

The inventive use may also be indicated for the prevention and controlof infections in humans and animals with other viruses of the order ofMononegavirales.

A negative antibody finding does not exclude a BDV infection and, withthat, an indication for the inventive treatment.

Since the mechanism of the adamantane action has not yet been clarified,it cannot be stated with certainty whether the action is causative orindirect.

1-Adamantane amine belongs to the group of adamantanes. These arestable, colorless, crystalline, tricyclic compounds with a “cage-like”structure. In its spatial structure, adamantane(tricyclo(3.3.1.1^(3,7))decane itself is similar to a diamond, is waterinsoluble and, for that reason already, pharmaceutically not usable.

There are, however, certain pharmaceutically usable adamantanederivatives.

From the PCT WO 94/28885, a plurality of adamantane derivatives areknown, which are substituted in different positions. These derivativesare, in particular, alcohols and ketones but do not includeamino-substituted derivatives. Numerous antiviral, antibacterial,antimycotic and antitumor properties, which are not quantified ingreater detail, are ascribed to these adamantane derivatives. Certainketones are said to be usable against HIV and possibly otherretroviruses.

The water-soluble salts of 1-adamantane amine or of 1-aminoadamantane(international name (INN): amantadine, C₁₀H₁₇N, MW 151.26), amantadinesulfate (II) and amantadine hydrochloride (III) have been known forabout 30 years as pharmaceutical active materials.

Amantadine sulfate or hydrochloride is still used at the present timefor the treatment of Parkinson's disease and in the further area of theParkinson syndrome in the case of an akinetic crisis, extrapyramidaldisorders and reduced vigilance. As far as it is known, thepharmacological effect is based, among other things, on an increase inthe availability of dopamine at the dopaminergic synapses. Details ofthe mechanism have not yet been clarified. On the basis of this effecton the nervous system, the use for the prophylactic treatment ofmigraines has also already being proposed (DE 19510189 A1).

Water-soluble amantadine derivatives were originally approved for theprophylaxis and treatment of certain influenza A strains. W. L. Davies,R. R. Grunert et al. (Science 1964, vol. 144, 862/863) discovered thatamantadine hydrochloride inhibits the replication of viruses of fourstrains of influenza A and one of the C type. On the other hand, theclosely related influenza B strains, mumps and a large number of otherRNA and DNA viruses were not sensitive. In the case of the A strains, itwas possible to push back the virus production by a power of 10, but itwas not possible actually to suppress it. Amantadine sulfate andamantadine hydrochloride were thereupon approved internationally as adrug for the prophylaxis of influenza A infections and for the treatmentof acute influenza diseases caused by influenza A viruses.

The specific activity of amantadine against influenza A virus isdocumented in vitro (cell culture) and on patients. The mechanism ofaction is based on the interaction of the substance with a membraneprotein, M₂, which is specific for the influenza A virus and is thusspecific for this virus. Influenza B viruses, which do not contain M₂protein, are not sensitive. By means of the prophylactic administration,the frequency and degree of severity of virus influenza, caused bycertain A viruses, are alleviated. If the substance is administered inthe first 24 to 48 hours after the occurrence of the influenza symptoms,the duration of the illness can be shortened (R. Dolin, R. C. Reichman,H. P. Madore, R. Maynard, P. N. Linton, J. Webber-Jones, N. Engl. J.Med. 1982, 307, 580-584; W. L. Wingfried, D. Pollack, R. R. Grunert, N.Engl. J. Med. 1969, 281, 579-584); A. J. Hay et al., Embo. J. 1985, 4,3021-3024; R. A. Lamb, S. L. Zebedee, C. D. Richardson, Cell 1985, 40,627-633). The virostatic effect against influenza thus is limited.

The French FR 6482M discloses also 2-adamantane amines with a similareffect as alternatives for 1-adamantane amines for the treatment ofinfluenza.

Because of the occurrence of amantadine-resistant influenza A strains(F. G. Hayden et al., N. Engl. J. Med. 1989, 121, 1696 to 1702) and thetherewith associated danger, as well as the possibility of a protectivevaccination for risk patients as alternatives, this area of indicationsof the drug (influenza) is practically no longer of any importance.

Surprisingly, it has now been discovered that amantadines showoutstanding actions against Borna viruses. Here amantadines areunderstood to be primarily 1-adamantane amine or its pharmaceuticallyjustifiable salts (such as amantadine sulfate, amantadine hydrochloride)as well as the 1-amino substituted, 1-alkylamino substituted or1-aminoalkyl substituted adamantanes or their salts (such asN-1-adamantyl-2-((2-dimethylamino)ethoxy) acetamide=tromantadine, or1-adamantyl-( 1-amino) ethane=rimantadine or their hydrochlorides orsulfates).

The outstanding anti-viral properties with respect to BDV are all themore surprising since chemotherapy of viral diseases is regarded in theliterature as being generally very difficult, since a causal treatmentalways seems to be problematical because of the “use” of the metabolismof the host cell (Mutschler, “Arzneimittelwirkungen” (Drug Actions) WVGStuttgart, 7^(th) Edition, 1996, pg. 725, 9.2.4).

Admittedly, it is known from the DE 39 21 062 A1 that 1-amantadinehydrochloride is said to be effective, however essentially only incombination with AZT, against HIV viruses by inhibiting viralreplication. The cyto-protective effect, which is achieved according toDE 40 14 672 A1 with certain 1-adamantane amine derivatives, goes in asimilar direction. However, it is a question here specifically ofeffects on retroviruses, which have a life cycle and manner orreplication, which is completely different from that of Borna diseaseviruses.

The Borna disease virus, BDV, is a sheathed RNA virus of 90 Nm diameter,which has a non-segmented, single-stranded genome of negative polarity,which codes for five viral genes (T. Briese, A. Schneemann, A. J. Lewis,et al., Proc. Natl. Acad. Sci. USA 1994, 91, 4362-4366). Related virusesare, for example, the measles virus and the rabies virus. Because of itsgenetic peculiarities (replication in the nucleus of the host cell andnot in the cytoplasm), the Borna virus is regarded as a prototype of itsown virus family (Bornaviridae) within the order of Mononegavirales.

BDV was first known as a pathogenic animal virus, which can initiateepisodic behavior disorder in animals. BDV strains from animals andhumans are genetically very similar (more than 95% sequence homology!).BDV has a particular preference for nerve cells of the limbic system inthe brain, which is responsible or co-responsible for behavioralcontrol, emotions and memory performance (H. Ludwig, L. Bode, G.Gosztony, Progr. Med. Virol. 1988, 35, 107-151; Dittrich W. et al.,Biol. Psychiatry 1989, 26, 818-828).

Presumably, due to the “activated” BDV infection, there are primarilyfunctional disorders in the area of the brain messenger materials ofthis system (G. Gosztony, H. Ludwig, Curr. Topics Microbiol. Immun.1995, 190, 39-73). BDV infections do not destroy the host cell; theypersist and are characterized by latent and activated phases. Especiallyduring the activity phases, there may be symptoms of the disease.

Water-soluble derivatives of L-adamantane amines inhibit the infectionwith Borna disease virus (in vitro, to the extent of 80%) and preventvirus replication in the already infected cells. The extent of thiseffect, described in greater detail in the examples, is exceptionallyhigh and completely unexpected. For the chemotherapy of viruses, suchgood virostatic results are unknown or very infrequent. The infectionpresumably was eliminated even completely (virus clearance, see below,Examples 2 and 3), this virocidal effect being totally surprising.

Furthermore, the materials, which are described here and claimed, act invivo as a highly efficient therapeutic agents for emotional diseases andfor disorders, which are related to BDV infections.

This effect is also extraordinarily and completely unexpected,especially in relation to the completeness of the elimination of thesymptoms and the rapid response to the treatment (in this connection,refer particularly to Example 4). If the inventive amantadine isadministered particularly during depressive episodes or during acutephases of other disorders associated with BDV infections, there is aclear and lasting improvement in the symptoms, such as has been observedwith other therapeutic agents only in very rare cases, already after afew days.

Medication with inventive amantadines accordingly, in the narrowersense, is indicated for BDV-infected patients with mood disorders,especially in the depressive phase and, in the wider sense, forBDV-infected patients with disorders, which are correlated with BDV,such as, for example, functional disorders of the limbic system orfunctional temporal lobe disorders, chronic fatigue syndrome, anxietydisorders, compulsive disorders and schizo-mood psychoses.

According to DSM-IV, medication with amantadines is indicated especiallyfor the following diagnosis numbers:

emotional disorders (mood disorders): 296.xx (particularly 296.3x,296.5x, 296.6x, 296.7x, 296.8x, 296.90); 300.3; 300.4; 311; 293.83;295.70; anxiety disorders, particularly in combination with adepression: 300.00; 300.02; 300.21; 300.22,

and, according to ISD-10, for the following diagnosisnumbers/categories:

mood disorders: F3 (especially F32, F33, F34, F38, F25); anxietydisorders: F41; compulsive disorders: F42.

The recommended dose for people is between 100 and 300 mg per day andpreferably 200 mg per day or 0.01 to 6 mg per kg of body weight per day.

The duration of the treatment (curative), assumed at the present time tobe meaningful, is 3 to 6 months.

The compounds, claimed pursuant to the invention, are also indicated forphase prophylaxis in the symptom-free interval for BDV-infected patientswith the above-described disorders. The preventative administration ofamantadines or corresponding effective materials is also indicated forhealthy persons, who live in close domestic contact with BDV-infectedpatients (human or animal) and/or have a genetic risk for developing oneof the above-described disorders.

The recommended dose for a prophylactic use is up to 200 mg per day andpreferably 100 mg per day for a duration of about 1 to 3 months.

Basically, all forms of administration, which make absorption possible,come into consideration. For example, parenteral, intramuscular,subcutaneous, intradermal or topical. The oral administration in theform of a powder, (film) tablets, coated pills, capsules or the like ispreferred. For certain applications, transdermal forms ofadministration, especially with a sustained release effect, such as apatch, come into consideration.

Amantadines generally are well tolerated. After oral administration,amantadine is absorbed almost completely. It is excreted in unchangedform through the kidneys. The half-lifetime is approximately 15 hours.For patients with renal insufficiency, preferably rimantadine isindicated, because it is metabolized in the liver and therefore theclearance of the drug does not depend on the function of the kidneys.

According to the present state of knowledge, the pharmacological actionis ascribed essentially to the adamantane structure, although themechanism is not yet known.

Therefore, water-soluble adamantane derivatives, such as the adamantaneamines named above, or their pharmacologically justifiable salts,especially N-(1-adamantyl)amines and (1-adamantyl)alkylamines or theirpharmacologically justifiable salts, basically are suitable for atreatment and prophylaxis in the sense of the invention.

Pursuant to the invention, amantadines can be used for the treatment ofemotional disorders in people and animals. It is known, in particular,that horses, sheep, cattle and also cats can suffer from persistentBorna virus infections and then also show mood disorders, that is,symptoms of psychological illnesses. Depending on the load, especiallyBDV-infected horses are in danger of developing behavioral disorderswith apathy as the main symptom and, without treatment, can becomefatally ill, especially in the case of fulminant virus production.

The treatment of animals can also be indicated epidemologically, inorder to inhibit BDV infections as a whole and to prevent the spreadingof such infections. Since the mechanism of transfer of the virus isstill unknown, such a treatment can also be regarded as a preventativemethod for maintaining human health.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 Inhibition of a BDV Infection with Amantadine Sulfate in vitro

Treatment of rabbit brain cells either with amantadine sulfate(continuous line) or meso-inositol (broken line) for one hour beforetheir infection (100±10 ffu/mL) with a human BDV strain (BDV-Hu1) *appropriate daily therapeutic dose of amantadine sulfate in mg,administered to the patient

FIG. 2 Inhibition of BDV replication by amantadine sulfate Decrease ininfectiousness 1) in human oligodendroglia (OL) cells, persistentlyinfected with BDV-Hu-H1, which were treated for 6 days with 1.2 μg/mL ofamantadine sulfate, and 2) in freshly infected OL cells, which weretreated with the same dose for 24 hours before the infection and thenfor a further 6 days, in comparison with untreated control samples.faded in: cell growth of not-infected OL cells with (solid line) andwithout (broken line) amantadine sulfate (1.2 μg)

FIG. 3 Virus Clearance After Treatment with Amantadine Sulfate isInterrupted

Decrease in virus titer in a human oligodendroglia (OL) cell line, whichwas freshly infected with BVD-Hu-H1, treated for 6 days with 1.2 μg/mLof amantadine sulfate and subsequently kept untreated (broken line) fora further 8 days and subjected to daily passages (1:2) in comparison tofreshly infected OL cells, which were, however, not treated over thewhole period.

DESCRIPTION OF THE WORKING EXAMPLE

In the following, the invention is illustrated by means of examplewithout limiting the universality.

EXAMPLES Example 1 In Vitro

Young rabbit brain cells were treated with amantadine sulfate and, in acomparison experiment, with meso-inositol. After this treatment, bothsamples were treated for 1 hour with a human Borna disease virus strain(100±10 ffu/mL with BDV-Hu-H1 (regarding this strain, refer also to L.Bode, et al., Mol. Psychiatry 1996, 1(3), 200-212)).

After this one-hour pre-treatment, amantadine sulfate, at aconcentration of only 0.019 μg/mL, inhibits the infection of rabbitbrain cells with human BVD to the extent of 50%. The highest in vitrodose, which permits normal, unimpaired cell growth, is 1.2 μg/mL,relative to the cell system.

The dose of 100 to 200 mg daily, which is recommended for patients witha different indication (Parkinson's syndrome) and the tolerance to whichhas therefore already been well tested, corresponds to a level of 0.2 to0.4 μg/mL, that is, to four-fold the dose, which is effective in vitro.

(In this connection, see FIG. 1)

Example 2 In Vitro

The inhibition of BDV application by amantadine sulfate was tested. Forthis purpose, human oligodendroglia cells (OL cells), persistentlyinfected with BDV-Hu-H1, were treated for 6 days in vitro with 1.2 μg/mLof amantadine sulfate. On the other side, freshly infected OL cells weretreated with the same drug dose for 24 hours and then for a further 6days after the infection. Even in already infected human oligodendrogliacells, the number of infectious viruses was reduced by a factor of morethan 10,000. The reduction in the virus titer to a level, at which BDVcan no longer be detected, is reached already after 2 days. Over thewhole of the period observed, the cell growth was practically notaffected by the dose used of 1.2 μg/mL of amantadine sulfate.

(See FIG. 2)

Example 3 In Vitro

The treatment of oligodendroglia cells, infected with human BDV, with1.2 μg/mL of amantadine sulfate in vitro was interrupted after 6 daysfor the following 6 days. The cells were subjected to passages everyday. A BDV infection could no longer be detected even after thetreatment-free interval. It can be concluded from this that not only thereplication (reproduction) of BDV is prevented very efficiently in thepresence of amantadine sulfate, but also that infected cells can befreed apparently permanently from the BDV infection by means ofamantadines (virus clearance).

(See FIG. 3)

Example 4 In Vivo

In the case of a 67-year old female patient with a bipolar disease(DSM-IV: 296.53), which has existed for 11 years, and frequent stays inhospital because of manic and severe depressive episodes, an activatedBDV infection was noted by detecting BDV proteins in leucocytes. Theblood analysis was conducted 3 months after the start of a severedepressive episode, which had not improved significantly underconventional therapy (including mianserine and valproate).

Initially, the patient received 50 to 100 mg of amantadine sulfate dailyon days 1 to 3, then 200 mg for 6 weeks followed by 100 mg for a further12 weeks and then 200 mg again for 2 weeks, until further provisions aremade. Her depression improved dramatically from the 8^(th) day to the11^(th) day under the treatment. After the 15^(th) day, it was possibleto discharge her from the hospital. After the 11^(th) day of thetreatment, and also 5 months later, Borna virus activity (proteinexpression in the blood leucocytes) could no longer be detected. Thepatient merely showed a low antibody titer against BDV.

The therapeutic effect was greater and significantly more rapid thanever before for results achieved with conventional anti-depressiondrugs. According to psychological test methods and subjective findings,the symptoms of depression are no longer present since the dramaticimprovement. Until now, there have been no undesirable side effects. Thepatient continues to do well.

According to this course of events, a prophylactic effect against manicphases also seems probable. Until 1993, an improvement in the depressionof the patient was followed directly by the manic phase, that is,without a disease-free interval. In the last 3 years, depressiveepisodes with subsequent hypomanic rebound effects predominated. Thelongest symptom-free interval was 4 months. Under amantadine therapy,the patient has now been depression-free for 5 months without ahypomanic rebound effect.

What is claimed is:
 1. A method for controlling viruses of theBornaviridae family, comprising an administration to human and animalsat a therapeutically effective dosage of up to about 10 mg/kg of bodyweight per day of adamantane amines against said viruses by a meansselected from the group consisting of oral, parenteral, intramuscular,subcutaneous, intradermal and topical means.
 2. The method of claim 1,wherein the viruses are the Borna disease virus in humans and animals.3. The method of claim 1, wherein the adamantane amine is present in theform of a pharmaceutical salt.
 4. The method of claim 1, wherein theadamantane amine is chosen from the group consisting of a 1-aminosubstituted, a 1-alkylamino substituted, a 1-aminoalkyl substitutedadamantane, and a pharmaceutical salt thereof.
 5. The method of claim 1,wherein the adamantane amine is a water soluble substance with theadamantane structure.
 6. The method of claim 1, wherein the dosage is 1to 4 mg/kg of body weight per day.
 7. The method of claim 3, wherein thepharmaceutical salt is selected from the group consisting of amantadinesulfate and amantadine hydrochloride.
 8. A method for the treatment ofemotional diseases caused by Borna disease virus infections in humans,comprising administering a therapeutically effective amount ofadamantane amines to the humans.
 9. The method of claim 8, wherein theemotional diseases are bipolar disorders.